Respiratory disorders are pulmonary conditions characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. During respiratory disorder episodes, afflicted individuals often experience labored breathing, wheezing, and coughing. These disorders may be treated by oral inhalation of medications such as beta adrenergic agonists or corticosteroids.
Inhaled corticosteroids (ICS) are corticosteroid medicaments that are designed for application directly to the tissues of the respiratory tract. ICS medicaments are the preferred treatment for long-term control of mild persistent, moderate persistent, or severe persistent asthma symptoms in children, teens, and adults. Corticosteroids provide highly effective treatment for chronic inflammatory disorders through a common mechanism that includes down-regulating the production of many inflammatory cytokines, chemokines, enzymes, and cell-adhesion molecules as well as inhibiting the activity of inflammatory mediators. Barnes (2003) Ann Intern Med 139:359-370. Corticosteroids also help control narrowing and inflammation in the bronchial tubes. The drugs used as ICS are very similar in action and use. Commercially available ICS medicaments include Aerobid (flunisolide, Roche), Azmacort (triamcinolone acetonide, Abbott), Flovent (fluticasone propionate, GlaxoSmithKline), Pulmicort (budesonide, AstraZeneca) and QVAR (beclomethasone dipropionate, TEVA Branded Pharmaceuticals).
Delivery systems that can administer ICS medicaments include nebulizers, dry powder inhalers (DPIs), and pressurized metered-dose inhalers (pMDIs). Nebulizer devices are a preferred delivery system when breathing strength or coordination is challenging. This is particularly true for children, elderly patients and patients with compromised breathing ability.
Drug formulations for oral inhalation delivery using nebulizers are aqueous solutions, dispersions or suspensions that are aerosolized and then inhaled. The aerosol comprises very fine droplets of the formulation dispersed in air. The droplets are necessarily less than about 5 microns in geometric diameter to provide respirable droplets that enable delivery of the aerosolized drug to the respiratory tract beyond the oropharynx upon inhalation. Aerosol generators, or nebulizers, apply mechanical shearing forces to the drug formulation by various means to break up the formulation surface or generate filament streams to form the droplets. Nebulizers typically use pneumatic, piezoelectric, ultrasonic, or electromechanical means to generate shearing forces. The nebulizers may also incorporate baffling mechanisms to remove larger, nonrespirable droplets from the aerosol. In use, the nebulized formulation is administered to the individual via a mouthpiece or mask.
Traditional nebulizer devices, such as jet nebulizers, are commonly used for ICS delivery. However, these devices require extended administration time lasting up to 30 minutes, often resulting in low patient compliance. In addition, the uniformity of the delivered dose from jet nebulizers can be challenging especially for suspension-based formulations. A particular group of nebulizers, referred to herein as “next generation nebulizers”, use meshes or membranes to produce fine droplet sprays. These devices are much more efficient at producing aerosols, and can significantly reduce administration time. The meshes/membranes in next generation nebulizers contain many apertures or pores that have diameters typically between 1 and 8 microns. The drug formulation is forced through the mesh apertures by piezoelectric or electromechanical “pumping” or, alternatively, the mesh is vibrated to reciprocate through a pool of the formulation, thereby generating multiple liquid filaments with diameters approximating the mesh apertures. The filaments breakup to form droplets with diameters approximating the diameters of mesh apertures. Next generation nebulizers which include, but are not limited to the AerX and Essence devices (Aradigm Coorp., Hayward, Calif.), the eFlow device (PARI Respiratory Equipment, Monterey, Calif.), the TouchSpray device (The Technology Partnership, Cambridge, UK), the Ineb and Myneb devices (Respironic, Andover, Mass.), the MicroAir device (Omron Healthcare, Inc., Vernon Hills, Ill.) and the Aeroneb device (Aerogen, San Francisco, Calif.) are very efficient aerosol generators that minimize the duration of administration. This is because next generation nebulizers can form aerosols that have a high proportion of respirable aerosol droplets, those with diameters much less than 4.7 microns mass median aerodynamic diameter (MMAD per compendial method USP 601), enabling quick and efficient delivery of the aerosolized drug to the respiratory tract.
Use of next generation nebulizers to deliver a suspension-based medicament presents significant pharmaceutical formulation challenges in regard to the need to enhance both delivery efficiency to the lungs and drug residence time in the lungs. The first challenge is the efficient delivery of the drug particles to the lung. This is primarily determined by the size of the largest dimension of the aerosol droplet population. The mean diameter of the aerosol droplet size distribution generated by the nebulizer must not exceed 4.7 microns MMAD to penetrate to the lungs. The drug particles need to be substantially smaller, less than 4 microns, than the droplets to be carried by the droplet aerosol into the lungs. Further the drug particles in the suspension must be able to pass through the small apertures of the nebulizer mesh/membrane in an efficient and reproducible manner. For example, while several commercial ICS products (e.g. Astra Zeneca's Pulmicort® or Teva's Budesonide Inhalation Suspension) have particles small enough to penetrate to the lung, they have low aerosolization efficiency when delivered using a next generation nebulizers such as the Aeroneb Go device (Aerogen). The drug particles in these suspension formulations are too large at circa 4 microns to easily pass through the mesh which has a mean aperture diameter of circa 3 microns. A majority of the particles are retained on the surface of the mesh and cannot pass through into the aerosol droplets. Such high drug particle retention is undesirable because the trapped particles block the flow of the formulation through the mesh and decrease the delivery rate, thus increasing both the drug delivery time and amount of drug loaded into the nebulizer necessary to achieve the required delivered dose. This results in higher treatment cost and long treatment times. In addition, the retained drug particles can mechanically interfere with operation of the next generation nebulizer by accumulating on the mesh, clogging the pores and eventually blocking drug output, which can disable the nebulizer. The retained drug may also affect consistency and uniformity of the delivered dose within a particular dosing session or when comparing across administration sessions.
The second challenge is achieving appropriate drug residence time in the lungs. Delivery of the drug to the lungs by itself is not sufficient to achieve treatment if the drug passes immediately through the lung to systemic circulations. Hockhaus, G. (2007)Annals of Allergy, Asthma and Immunology 98:S7-S15. Prolonging the residence time in the lung will increase pulmonary receptor selectivity to treat local inflammation and lower undesirable systemic receptor side effects such as endogenous hormone generation and resulting growth suppression. Suarez et al. (1998) Pharm Res. 15:461-465. This is primarily determined by the lipophilicity of the drug, and the effective surface area of the drug particle population, where individual particle size and morphology are the chief variables. Since most glucocorticosteroids have relatively similar lipophilicity, the drug particles used in ICS formulations need to have a morphology that combines a minimum specific surface area (SSA) with the largest possible particle size. Reduction in the SSA of each drug particle, and thus the effective surface area of the particle population, lowers the dissolution rate of the drug in epithelial lining fluid and lung tissue, thereby increasing residence time in the targeted biospace. The easiest way to reduce surface area of a particle population is to increase the size of the individual particles, but this is in direct conflict with reducing the drug particle size to enable nebulizing with a next generation mesh/membrane nebulizer. Increases in the particle size that result in a particle dimension approaching or exceeding the size of the apertures in the mesh/membrane will reduce delivery efficiency. Decreases in the particle size, such as molecular-complex solutions, submicron or nanometer particle size suspensions to accommodate passage through the mesh/membrane will markedly decrease particle residence time in the lungs.
The most commonly used techniques for producing particles for use in ICS formulations are traditional micronization processes. See, e.g., U.S. Pat. Nos. 5,510,118; 5,518,187; 5,718,388; and 5,862,999. Prolonged grinding as occurs in micronizing comminution results in a high energy powder and crystal lattice defects which lowers physicochemical stability by making the particle susceptible to crystallinity shifts and chemical degradation. In addition, micronization processes usually produce particles having irregular shapes and wide particle size distributions. Accordingly, even though the SSA of a particle produced using micronization techniques can be relatively low, the particle size distribution in the population is too broad, and there are an unacceptably high amount of large particles produced that will be retained on the nebulizer mesh when administered by next generation nebulizers, resulting in low delivery efficiency.
Precipitation processes can also be used to generate particles as described in U.S. Pat. No. 6,221,398. However, optimum crystal structure formation and optimum purity may not be obtained in precipitation processes. It is difficult to control particle size and distribution by precipitations processes without resorting to high shear regimes. Finally residual solvent in the particles can lead to changes in crystallinity, particle size and shape, and/or chemical stability.
Because micronization or precipitation also results in some amorphous regions in the resulting particles, a “conditioning” step as described in U.S. Pat. No. 5,709,884 or U.S. Pat. No. 5,874,063 is necessary in order to obtain a particle considered to be completely crystalline. In these processes, conditioning the comminuted or precipitated particles with water or organic vapors reduces stored energy in the particles, induces crystallization of amorphous regions and reduces specific surface area of the particles to 3-10 meter2/gram.
Another technique that can be used to produce particles for ICS formulations is supercritical fluid technology. See, e.g., Velaga et al. (2002) Pharmaceutical Research 19(10):1564-1571; and Steckle et al. (2004) European Journal of Pharmaceutics and Biopharmaceutics 57:507-512. Use of supercritical fluid particle formation processes can produce regularly shaped, partly spherical particle morphologies, the process parameters need to be carefully monitored to obtain reproducible results. In addition, supercritical fluid techniques are typically quite complex, have limited batch sizes, and are expensive and usually challenging to scale-up. Solvent/anti-solvent precipitation techniques have also been used to produce ICS (budesonide) particles with various morphologies such as flakes, spindles, ellipsoids and octahedrons. See, e.g., Hu et al. (2008) Ind. Eng. Chem. Res. 47:9623-9627 and Ruch et al. (2000) Journal of Colloid and Interface Science 229:207-211. However, the particles produced by such precipitation methods have a relatively high aspect ratio and SSA and are thus expected to have a reduced residence time in the lungs.
Accordingly, there remains a need in the art for improved glucocorticosteroid particles for use in ICS formulations, where the formulations exhibit enhanced delivery efficiency when administered using a next generation nebulizer device, and the particles also have selected physicochemical properties (crystallinity, shape, specific surface area and energy, size and size distribution) that provide for optimum delivery to the lung and to increase residence time in the lungs after administration. There further remains a need in the art for a simplified, reproducible and scalable particle formation process that can produce glucocorticosteroid particles having a narrow particle size and shape distribution, low aspect ratio and a uniform particle morphology that reduces the particle SSA.